Infections of the central nervous system present the most significant challenge in our attempt to combat infectious diseases. Part of our inability to counter these diseases is attributed to an incomplete understanding of (i) how infectious agents cross the blood-brain barrier, a key step in the development of CNS infections, and (ii) the inability of drugs to traverse the blood-brain barrier to gain entry into the brain to kill parasites. Thus, there is an urgent need to expedite both drug discovery and drug delivery programmes. Here, we describe the use of in vitro, ex vivo, and in vivo models of the blood-brain barrier to examine the physical barriers, cellular mechanisms and molecular elements participating from both sides of the parasite-host interactions. In addition, these models provide useful screening tools to give rough indications of the potential of new antimicrobial agents with respect to efficacy, optimal routes of administration, and toxicity.